A migraine is a type of a headache with characteristic throbbing pain which may occur with symptoms such as nausea, vomiting, or sensitivity to light. In the United States, more than 37 million people suffer from migraines and almost 5 million experience at least one migraine attack per month. The World Health Organization ranks migraines as the 19th most common reason for disability. The loss of productivity due to migraines is estimated to be between $5.6 billion to $17.2 billion per year because of missed work. See, Miles et al. “Migraine statistics,” November 2010. Drugs commonly prescribed for the treatment of migraines include narcotic analgesics (oxycodone), nonsteroidal anti-inflammatory drugs (ibuprofen), barbiturates (butalbital), ergot derivatives (dihydroergotamine), selective 5-HT receptor agonists (sumatriptan) and antiemetics (prochlorperazine). See, Zhang et al., Ann Transl Med. 2016; 4(6): 105; Goadsby et al., Nat Rev Neurol. 2015; 11(11): 621-2. A major drawback with the frequent use of narcotics is the risk of physical dependence and the “interdose withdrawal” phenomenon, which can lead to more migraines (Peroutka et al., Headache. 1990; 30(1 Suppl): 5-11; discussion 24-8; Jones et al., Ann Emerg Med. 1994; 24(2): 237-41). The chronic use and abuse of ergot alkaloids can result in ergot-induced headaches, which can worsen nausea and vomiting associated with a migraine as well as increase the risk of ergotism (Jones et al., supra; Kudrow et al., Adv Neurol. 1982; 33: 335-41). Even though therapy involving sumatriptan meets the majority of patient needs, patients often are not satisfied due to the development of rebound headaches, persistent nausea, vomiting, and gastric stasis (Sharma et al., Headache. 2002; 42(9): 896-902; Zed et al., Ann Pharmacother. 1999; 33(1): 61-72). This dissatisfaction indicates a clear need for alternative treatments for acute therapy of migraine headaches.
Prochlorperazine belongs to the piperazine subclass of phenothiazines and is widely used as an anti-emetic and anti-psychotic agent (Khatri et al., Headache. 2009; 49(3): 477-80). The most common degradation pathways of prochlorperazine involve oxidation and photodegradation resulting in sulfoxides as the major degradation products. Prochlorperazine is also used for migraines, and comparative clinical studies have shown that prochlorperazine provides better pain relief than sumatriptan, metoclopramide, and ketorolac (Jones et al., Am J Emerg Med. 1996; 14(3): 262-4; Seim et al., Acad Emerg Med. 1998; 5(6): 573-6; Donohue et al., Ann Emerg Med. 1995; 25: 154-55). Prochlorperazine was also shown to be highly effective in the treatment of acute confusional migraine which is a rare migraine variant primarily seen in childhood that lacks standardized diagnostic criteria (Khatri et al., Headache. 2009; 49(3): 477-80). For the treatment of acute migraine, prochlorperazine is usually administered at doses 10 mg by intravenous or intramuscular route and, 25 mg by oral or rectal route (Gelfand et al., Neurohospitalist. 2012; 2(2): 51-59). The exact mechanism of prochlorperazine for migraines is unknown. However, it is believed that prochlorperazine may exert effects for migraines by a combination of actions including anti-serotonin effects, anti-dopamine effects in the chemoreceptor trigger zone, and vascular effects through their α-blocking action (Lance et al., Pathol Biol (Paris). 1992; 40(4): 355-60). In all clinical trials discussed above, prochlorperazine was administered parenterally (intravenous, intramuscular, etc.) which is an expensive and cumbersome route of administration requiring medical intervention in a clinical setting.
The drawbacks of low and variable absorption and high first-pass metabolism limit administration of prochlorperazine by the oral route (Finn et al., J Clin Pharmacol. 2005; 45(12): 1383-90). Although nasally administered antiemetic formulations containing metoclopramide, ondansetron, granisetron, domperidone, dimenhydrinate and/or promethazine have been described in literature (Ozsoy et al., Expert Opin Drug Deliv. 2011; 8(11): 1439-53), they are formulated with a host of polymers such as poloxamer 405, pluronic 127, gellan gum, sodium carboxymethyl cellulose, carbopol 981, chitosan, etc., binders and solvents such as hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium alginate, bile salts, protamine sulfate and poly-L-arginine, and other permeation enhancers (see, Ozsoy et al.). This review article is silent as to the unique advantages offered by aqueous formulations containing chlorperazine and the carriers described herein, including, ease of extemporaneous formulation and/or administration.
In certain instances, prochlorperazine may also be administered intravenously, parenterally or bucally; however, each route of administration is associated with numerous drawbacks. For instance, prochlorperazine, when administered intravenously, displays dose-dependent extrapyramidal side effects such as akathisia and tardive dyskinesia (Drotts et al., Ann Emerg Med. 1999; 34(4 Pt 1): 469-75). Parenteral administration is frequently associated with needle-stick injuries (Corrigan et al., Am J Health Syst Pharm. 2015; 72(18): 1544-54). In contrast to the existing modes of delivery, the instant invention contemplates that intranasal administration may offer several advantages, including, mitigating the risk of injuries; allowing self-treatment by patients for continuous therapy supplementing intravenous treatment in the emergency room; and reduction in extrapyramidal side effects due to delivery of high concentration of the drug at the target site (e.g., brain). Due to these potential benefits, intranasal administration of prochlorperazine may be an attractive alternative therapeutic option for treatment of an acute migraine in human patients.
Because nasally-administrated prochlorperazine comes into direct contact with the soft tissues of the nasal mucosa, aqueous-based nasal sprays are preferably formulated as sterile formulations. Other anti-emetic nasal sprays are frequently formulated with preservatives such as benzalkonium chloride, methyl paraben, propyl paraben and phenylcarbinol, etc., which prevent antimicrobial contamination in (Batts et al., J Pharm Pharmacol. 1989; 41(3): 156-9). However, clinical evidence shows that preservatives such as benzalkonium chloride and phenylcarbinol may cause local mucosal hypersensitivity, including toxic effects such as sinonasal mucosal injury, nasal squamous metaplasia, and genotoxicity (Ho et al., Am J Rhinol. 2008; 22(2): 125-9; Deutschle et al., Toxicol In vitro. 2006; 20(8): 1472-7; Larsen et al., Food Chem Toxicol. 2003; 41(3): 439-46; Grummt et al., Environ Mol Mutagen. 2006; 47(2): 95-106). Thus, a need exists for formulating nasal sprays without the use of chemical preservatives, wherein the formulations have reduced toxicity compared to preservative-containing formulations, but are bioequivalent with respect to the desired pharmacological effects (e.g., potency, efficacy, etc.) even after storage for prolonged periods of time.